Type I diabetes is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells following infiltration of the islet by lymphocytes. This results in insulin deficiency.
Apoptosis is the primary mode of beta cell death during development of Type-1 diabetes (O′Brien et al. (1997) Diabetes 46:750-57). IL-1, TNF-alpha and IFN-gamma are released by T cells and macrophages during this autoimmune response and are important mediators of beta cell destruction (Eizirik and Mandrup-Poulsen (2001) Diabetologia 44:2115-2133).
Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) induces apoptosis in a manner unrelated to its IGF binding (Rajah et al. (1997) J Biol. Chem. 272:12181-88). Pro-inflammatory Th1 cytokines increases intranuclear aggregation of endogenous IGFBP-3 and addition of exogenous IGFBP-3 to beta cells induces apoptosis (Shim et al. (2004) Growth Horm IGF Res. 14:216-25). IGFBP-3 is one of a number of peptides that includes insulin, leptin, adiponectin, and resistin, that have been shown to act in the central nervous system to regulate glucose metabolism (Muse et al. (20070 J Clin Invest. 117:1670-78; Obici et al. (2002) Nat Med 8:1376-82). Beta cell loss by apoptosis also occurs after islet graft (Paraskevas et al. (1999) FEBS Lett. 455:203-8); Tobiasch et al. (2001) J Investig Med. 49:566-71). Recent studies have demonstrated that isolated human islets express the pro-apoptotic protein Bax at higher level than the anti-apoptotic protein Bcl-2 (Thomas et al. (2002) Transplantation 74:1489).
Over a million people in the U.S. have type I diabetes. According to the American Diabetes Association, the disease causes thousands of deaths every year and costs more than $20 billion annually. There is currently no effective therapeutic or preventative agent available for Type I diabetes.
Humanin (HN) is a recently described 24-amino acid peptide. HN was independently cloned as a neuroprotective protein, a BAX antagonist, and as an IGFBP-3 binding partner in a yeast two-hybrid assay (Hashimoto et al. (2001) Proc. Natl. Acad. Sci. USA 98:6336-41; Guo et al. (2003) Nature 423:456-61; Ikonen et al. (2003) Proc. Natl. Acad. Sci. USA 100:13042-47). HN is transcribed from an open reading frame within the mitochondrial 16S ribosomal RNA in mammals (Hashimoto et al., 2001). HN is both an intracellular and secreted protein. HN has been detected in normal mouse testis and colon (by immunoblot and immunohistochemical analyses), as well as in cerebrospinal fluid (CSF), seminal fluid, and serum. Levels in CSF are few orders of magnitude higher than that in circulation. Similar or identical HN cDNA sequences have since been identified in plants, nematodes, rats, mice, and many other species, demonstrating that it is highly conserved along evolution (Guo et al., 2003).